An evaluation of reference tissue normalization in quantitative ¹⁸F-NaF PET/CT

Objectives: Quantitative ¹⁸F-NaF PET/CT imaging has shown potential as a tool for identifying and monitoring malignant bone disease. However, natural fluctuations of ¹⁸F-NaF PET uptake within diseased and normal tissue have been observed. The aim of this study was to evaluate intra-patient variable uptake and evaluate the applicability of reference tissue normalization in quantitative ¹⁸F-NaF PET/CT.

Methods: Thirty-three metastatic castrate-resistant prostate cancer patients received whole body test-retest scans prior to therapy. Our in-house Quantitative Total Bone Imaging software was used to identify, segment, and match NaF-avid bone lesions between scans using bone-specific SUV thresholds. Mean uptake was derived from whole healthy skeleton (SUV_skel), normal bone regions (SUV_bone), and normal tissue regions (SUV_tissue). To assess if fluctuations in normal uptake correlated with fluctuations in diseased uptake, linear mixed effects models were used to model the relationship between relative mean difference (RMD) of normal uptake with lesion SUVs. RMD of lesion SUVs was then reassessed following normalization by normal uptake. Intra-patient repeatability was measured with the 95% limits of agreement (LOA).

Results: A total of 601 lesions were identified in the bone; both SUV_max (LOA: 1.01 [0.76, 1.35]) and SUV_mean (LOA: 1.00 [0.87, 1.16]) were derived from individual lesions. RMD of SUV_skel was not correlated to RMD of lesion SUVs. RMDs of SUV_tissue, in regions such as in the liver and brain, were not correlated to RMD of lesion SUVs. RMDs of SUV_bone, in regions such as the lumbar spine and pelvis, were similar across all regions. RMD of lesion SUV_mean was not correlated to SUV_bone. RMD of lesion SUV_max was correlated to RMD of SUV_bone (P = 0.02); however, the magnitude of this correlation was small. When SUV_bone was used as reference regions to normalize lesion SUV_max, measurement repeatability degraded (LOA: 1.00 [0.69, 1.45]).

Conclusion: Variable tracer uptake across the whole healthy skeleton, within normal bone regions, and within normal tissue regions was poorly or not correlated to the variability in lesion uptake. Since reference tissue normalization is only useful when variations in reference region uptake and variations in diseased tissue uptake are linearly correlated, reference region normalization for quantitative ¹⁸F-NaF PET is not appropriate. Research Support: This study supported by Prostate Cancer Foundation Creativity Award, PCF Mazzone Challenge Award, and DOD PCRP Clinical Consortium Award, and conducted within the Prostate Cancer Clinical Trials Consortium.

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